Asthma is a common, severe, and debilitating medical condition. The prevalence of asthma and asthma-related morbidity and mortality has increased in recent years. Data suggest that depressive symptoms and disorders are common in asthma patients and may be a risk factor for asthma-related morbidity. However, minimal data are available on the treatment of persons with depression and asthma. We initiated a research program on the interactions between asthma and depression. Pilot data were collected looking at the efficacy of citalopram versus placebo in outpatients with major depressive disorder and asthma. The goal was to establish feasibility and safety, determine appropriate outcome measures, and identify patient groups most responsive to the antidepressant therapy. The group receiving citalopram showed greater sustained remission of depressive symptoms and required significantly less oral corticosteroids for asthma symptom control than the group receiving placebo. Change in depressive symptom severity was associated with positive change in asthma-related outcomes. Remitters from depression had greater improvement in scores on measures of asthma symptom control and asthma-related quality of life, and required less as-needed bronchodilator use. Thus, improvement in depression was associated with improvement in asthma. A subsample with more severe depression and frequent oral corticosteroid use showed positive changes in depressive and asthma symptoms and less oral corticosteroid use, all favoring the antidepressant group. We now propose a definitive antidepressant trial, in response to the R18 announcement, in outpatients with asthma and major depression based on pilot study information gained regarding effect sizes, predictors of response, and sensitivity of outcome measures. A 12-week randomized, double-blind, placebo-controlled, acute phase trial of escitalopram is proposed in 80 outpatients with asthma and major depression with a baseline Hamilton Rating Scale for Depression score of e 20 and who frequently require oral corticosteroids and in a group of 142 depressed asthma patients with less severe depression and/or less frequent corticosteroid use. A 12-week continuation phase for depression responders is also proposed. Changes in Asthma Control Questionnaire scores (primary outcome measure), oral corticosteroid use, depressive symptoms, quality of life, and asthma medication adherence will be assessed as well as the relationship between changes in depressive and asthma symptom severity. A research team with expertise in depression clinical trials, mood disorders, asthma, and statistics will conduct the trial. The findings will have implications for asthma treatment.